Gottfried 2013 PLoS One: Difference between revisions
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|year=2013 | |year=2013 | ||
|journal=PLoS One | |journal=PLoS One | ||
|abstract=Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Dc significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor ฮฑ-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies. | |abstract=Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Dc significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation ''in vitro'' and reduced melanoma growth ''in vivo''. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor ฮฑ-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies. | ||
|keywords= | |keywords=Diclofenac, Myc, Glucose metabolism, Melanoma, Leukemia, Carcinoma | ||
|mipnetlab=DE Regensburg Renner-Sattler K | |editor=[[Gnaiger E]], | ||
|mipnetlab=DE Regensburg Renner-Sattler K, DE Regensburg Renner-Sattler K | |||
}} | }} | ||
{{Labeling | {{Labeling | ||
|area=Respiration, Pharmacology;toxicology | |area=Respiration, Pharmacology;toxicology | ||
|diseases=Cancer | |||
|organism=Human, Mouse | |organism=Human, Mouse | ||
|tissues=Endothelial; | |tissues=Endothelial;epithelial;mesothelial cell, Blood cells, Other cell lines, Lymphocyte | ||
|preparations=Intact cells | |preparations=Intact cells | ||
|couplingstates=LEAK, ROUTINE, ET | |||
|couplingstates=LEAK, ROUTINE, | |||
|instruments=Oxygraph-2k | |instruments=Oxygraph-2k | ||
|additional=Leukemia, Diclofenac, Aspirin, | |||
}} | }} |
Latest revision as of 08:54, 21 February 2020
Gottfried E, Lang SA, Renner K, Bosserhoff A, Gronwald W, Rehli M, Einhell S, Gedig I, Singer K, Seilbeck A, Mackensen A, Grauer O, Hau P, Dettmer K, Andreesen R, Oefner PJ, Kreutz M (2013) New aspects of an old drug - Diclofenac targets MYC and glucose metabolism in tumor cells. PLoS One 8:e66987. |
Gottfried E, Lang SA, Renner K, Bosserhoff A, Gronwald W, Rehli M, Einhell S, Gedig I, Singer K, Seilbeck A, Mackensen A, Grauer O, Hau P, Dettmer K, Andreesen R, Oefner PJ, Kreutz M (2013) PLoS One
Abstract: Non-steroidal anti-inflammatory drugs such as diclofenac exhibit potent anticancer effects. Up to now these effects were mainly attributed to its classical role as COX-inhibitor. Here we show novel COX-independent effects of diclofenac. Dc significantly diminished MYC expression and modulated glucose metabolism resulting in impaired melanoma, leukemia, and carcinoma cell line proliferation in vitro and reduced melanoma growth in vivo. In contrast, the non-selective COX inhibitor aspirin and the COX-2 specific inhibitor NS-398 had no effect on MYC expression and glucose metabolism. Diclofenac significantly decreased glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 1 (MCT1) gene expression in line with a decrease in glucose uptake and lactate secretion. A significant intracellular accumulation of lactate by diclofenac preceded the observed effect on gene expression, suggesting a direct inhibitory effect of diclofenac on lactate efflux. While intracellular lactate accumulation impairs cellular proliferation and gene expression, it does not inhibit MYC expression as evidenced by the lack of MYC regulation by the MCT inhibitor ฮฑ-cyano-4-hydroxycinnamic acid. Finally, in a cell line with a tetracycline-regulated c-MYC gene, diclofenac decreased proliferation both in the presence and absence of c-MYC. Thus, diclofenac targets tumor cell proliferation via two mechanisms, that is inhibition of MYC and lactate transport. Based on these results, diclofenac holds potential as a clinically applicable MYC and glycolysis inhibitor supporting established tumor therapies. โข Keywords: Diclofenac, Myc, Glucose metabolism, Melanoma, Leukemia, Carcinoma โข Bioblast editor: Gnaiger E โข O2k-Network Lab: DE Regensburg Renner-Sattler K, DE Regensburg Renner-Sattler K
Labels: MiParea: Respiration, Pharmacology;toxicology
Pathology: Cancer
Organism: Human, Mouse Tissue;cell: Endothelial;epithelial;mesothelial cell, Blood cells, Other cell lines, Lymphocyte Preparation: Intact cells
Coupling state: LEAK, ROUTINE, ET
HRR: Oxygraph-2k
Leukemia, Diclofenac, Aspirin